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Viral-Mediated Connexin 26 Expression Combined with Dexamethasone Rescues Hearing in a Conditional Gjb2 Null Mice
Xiaohui Wang1, Li Zhang1, Sen Chen1
1Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Abstract:
GJB2 encodes connexin 26 (Cx26), the most commonly mutated gene causing hereditary non-syndromic hearing loss. Cx26 is mainly expressed in supporting cells (SCs) and fibrocytes in the mammalian cochlea. Gene therapy is currently considered the most promising strategy for eradicating genetic diseases. However, there have been no significant effects of gene therapy for GJB2 gene mutation-associated deafness because deficiency of Cx26 leads to expanded sensory epithelial damage. In this study, the AAV2.7m8 serotype combined with the gfaABC1D promoter targeted infection of SCs is identified. It is found that Gjb2 gene replacement therapy in wild-type mice results in sensory hair cells (HCs) deficits, excessive inflammatory responses, and hearing loss. This may be one of the key factors contributing to the hardship of GJB2 gene replacement therapy. Dexamethasone (DEX) shows promising results in inhibiting macrophage recruitment, with a protective effect against HC damage. Further, the combination of AAV2.7m8-Gjb2 with DEX shows a synergistic effect and enhances the gene therapy effect in a conditional Cx26 null mice model. These results indicate that the combination of gene therapy and medication will provide a new strategy for the treatment of hereditary deafness associated with GJB2 defects.
Insights
Gene therapy for connexin 26 (Cx26) hearing loss faces challenges due to inflammation. Combining GJB2 gene therapy with dexamethasone (DEX) shows synergistic effects, offering a new strategy for treating hereditary deafness.
Area of Science:
- Genetics
- Otolaryngology
- Molecular Therapy
Background:
- GJB2 mutations causing connexin 26 (Cx26) deficiency are a leading cause of hereditary non-syndromic hearing loss.
- Cx26 is crucial for cochlear function, primarily in supporting cells and fibrocytes.
- Current gene therapy approaches for GJB2-associated deafness are hindered by inflammatory responses and sensory damage.
Purpose of the Study:
- To investigate the efficacy of AAV2.7m8-mediated GJB2 gene replacement therapy in the cochlea.
- To evaluate the impact of dexamethasone (DEX) on inflammation and hair cell protection during gene therapy.
- To explore a combined gene therapy and pharmacological approach for treating GJB2-related hearing loss.
Main Methods:
- Utilized AAV2.7m8 serotype with the gfaABC1D promoter for targeted gene delivery to supporting cells.
- Administered Gjb2 gene replacement therapy in wild-type and conditional Cx26 null mice models.
- Assessed hair cell integrity, inflammatory responses, and hearing function post-treatment.
- Investigated the effects of dexamethasone (DEX) on macrophage recruitment and hair cell damage.
Main Results:
- Gjb2 gene replacement alone in wild-type mice led to hair cell deficits, inflammation, and hearing loss.
- Dexamethasone (DEX) effectively inhibited macrophage recruitment and protected against hair cell damage.
- The combination of AAV2.7m8-Gjb2 and DEX demonstrated synergistic effects, enhancing therapeutic outcomes in Cx26 deficient mice.
Conclusions:
- GJB2 gene replacement therapy can induce adverse inflammatory reactions and sensory deficits.
- Dexamethasone (DEX) mitigates inflammation and protects cochlear hair cells.
- Combining AAV2.7m8-Gjb2 gene therapy with DEX presents a promising synergistic strategy for treating GJB2-associated hereditary deafness.
